TGFβ signalling is required to maintain pluripotency of human naïve pluripotent stem cells

eLife

Christel Krueger¹  Simon Andrews¹  Amanda J Collier²  A Sophie Brumm³  Kathy K Niakan⁴  Ludovic Vallier⁵  Brandon T Wesley⁵  Anna Osnato⁵  Daniel Ortmann⁵  Stephanie Brown⁵  Mariana Quiroga Londoño⁵  Shota Nakanoh⁶  Daniele Muraro⁷  Peter J Rugg-Gunn⁸ 

[1] Bioinformatics Group, The Babraham Institute, Cambridge, United Kingdom;Epigenetics Programme, The Babraham Institute, Cambridge, United Kingdom;Human Embryo and Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom;Human Embryo and Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom;Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom;Wellcome–MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, United Kingdom;Department of Surgery, University of Cambridge, Cambridge, United Kingdom;Wellcome–MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, United Kingdom;Department of Surgery, University of Cambridge, Cambridge, United Kingdom;Division of Embryology, National Institute for Basic Biology, Okazaki, Japan;Wellcome–MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, United Kingdom;Department of Surgery, University of Cambridge, Cambridge, United Kingdom;Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom;Wellcome–MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, United Kingdom;Epigenetics Programme, The Babraham Institute, Cambridge, United Kingdom;Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom;

关键词: pluripotent stem cells;    embryonic stem cells;    gene regulation;    Human;   

DOI  :  10.7554/eLife.67259

来源: eLife Sciences Publications, Ltd

【 摘 要 】

The signalling pathways that maintain primed human pluripotent stem cells (hPSCs) have been well characterised, revealing a critical role for TGFβ/Activin/Nodal signalling. In contrast, the signalling requirements of naive human pluripotency have not been fully established. Here, we demonstrate that TGFβ signalling is required to maintain naive hPSCs. The downstream effector proteins – SMAD2/3 – bind common sites in naive and primed hPSCs, including shared pluripotency genes. In naive hPSCs, SMAD2/3 additionally bind to active regulatory regions near to naive pluripotency genes. Inhibiting TGFβ signalling in naive hPSCs causes the downregulation of SMAD2/3-target genes and pluripotency exit. Single-cell analyses reveal that naive and primed hPSCs follow different transcriptional trajectories after inhibition of TGFβ signalling. Primed hPSCs differentiate into neuroectoderm cells, whereas naive hPSCs transition into trophectoderm. These results establish that there is a continuum for TGFβ pathway function in human pluripotency spanning a developmental window from naive to primed states.

【 授权许可】

CC BY